Although radiation is harmful to all tissues, malignant or healthy, most cancer cells lack control over DNA repair mechanisms. One of the greatest challenges of radiotherapy, for example in the treatment of cancer, is to minimize damage to normal cells while delivering a sufficient dose to kill tumor cells.
The main advantage of Proton beam therapy (“PBT”) over conventional radiotherapy (“RT”) is the more precise geometrical shape of the energy deposition inside the patient. The Bragg peak at the end of the proton range allows delivery of an accurate dose in a deep seated cancer, which also reduces the dose to surrounding normal tissues. The proton beam causes higher density of ionization events along its track, which can result in irreparable damage. The irreparable damage is more apparent at the end of the beam path and is the origin of the enhanced biological efficiency in the Bragg peak region. This biological efficiency is called Relative Biological Effectiveness (“RBE”) and depends upon many biological and physical parameters.
Many techniques have been developed in order to protect normal tissue and maximize dose to the tumor using photon-based conventional radiotherapy. Three-Dimensional Conformal Radiation Therapy (“3D-CRT”) uses several shaped beams converging in the tumor to reduce the dose on surrounding cells and nearby structures. Intensity Modulated Radiation Therapy (“IMRT”) uses a multi-leaf collimator to enable modification of the photon fluence within the target while delivering non-coplanar 3D-CRT. Stereotactic Radiosurgery (“SRS”) and Stereotactic Body Radiotherapy (“SBRT”) may be coplanar or non-coplanar, use high doses per fraction, and are generally delivered to small (˜10 cm) targets.
The depth of maximum dose thereby increases with energy. Beyond the maximum depth dose, beam hardening shifts the energy profile and higher energy leads to greater penetrating power. Absorbed dose is defined as the average energy of ionizing radiation absorbed per unit mass (dE/dm). To calculate dose deposition in tissue, the photons and secondary electrons, which result from the physical interactions, are traced voxel-by-voxel. Also, the probability of tissue ionization of each type of interaction τ/ρ, κ/ρ, σ/ρ sum, resulting in the mass energy absorption [μ/p].
The RBE can often be measured by cell survival experiments in-vitro or by biophysical models. Proton radiation has been shown to be more biologically effective for cell killing compared with X-rays for human tissue because of the higher density of ionization tracks. Clinically to date, RBE of 1.1 (WRBE=1.1) is applied to all treatments independent of dose/fraction, position in the Spread Out Bragg Peak (“SOBP”), initial beam energy and the tissue type. However several studies reported that the RBE depends on the Dose-averaged Linear Energy Transfer (“LETd”), cell or tissue type which is a function of its (α/β)x, and the dose per fraction. The variations of LETd values have been observed within the exposure volume in proton treatment. The RBE values are directly proportional to LETd and inversely proportional to (α/β)x. These dependencies make the RBE values vary from point to point along the proton track, especially where an SOBP is employed to treat the planning target volume (“PTV”) region.
The increase in RBE of proton beams at the distal edge of the SOBP is a well-known phenomenon that is difficult to quantify accurately in vivo. For purposes of treatment planning, disallowing the distal SOBP to fall within vulnerable tissues hampers sparing to the extent possible with proton beam therapy (“PBT”).
In treatment planning, any potential variation of RBE over the SOBP could result in biological hot spots with wide variations in biological dose that make dosimetry difficult.
Reviews of radiobiological data indicate that an RBE of 1.1-1.2 should be used to calculate the biological dose, Dbio, of proton radiation. However several studies suggest that the RBE is not a constant along the depth dose profile of the SOBP. The Bethe-Bloch equation describes an increase in stopping power as energy decreases. Therefore as depth of proton increases, the LET increases; and up to 100 keV/μm RBE increases.
Many published studies suggest that from the midpoint to the distal side of SOBP, the RBE value increases to a maximum of about 3. The RBE value increases from 1.1 at the absorber entrance to as much as 1.6 at the distal half of the SOBP plateau and to as much as 2.9 in the Distal Dose Fall-off (“DDF”).
Thus, while in the art there is an understanding of the dose deposition physics of charged particle irradiation, there is an insufficient understanding of the biological responses to that energy absorption. Because biological response drives the clinical prognosis, the uncertainty needs to be resolved by using relative biological effectiveness in treatment planning for the application of radiation proton therapy.
The physics of proton therapy provides significant advantages over x-ray therapy in certain cases. For example children benefit from the increased conformity of dose delivery that minimizes dose to healthy tissue and reduces complications and the occurrence of secondary cancers. Proton therapy is also useful in cases of retreatment of recurrent tumors for similar reasons. Nonetheless, no therapy is both totally effective and without risk. As medicine strives toward this goal, the biological effects of each therapy must be understood and controlled. The treatment techniques used in the past will not be sufficient in the future.